Efficient strategy for the synthesis of stereopentad subunits of scytophycin, rifamycin S, and discodermolide.

Article abstract of DOI:10.1021/ol016250h

[reaction: see text] An efficient, simple method has been developed for the stereocontrolled synthesis of polypropionate stereopentads in high enantio- and diastereomeric purities.

Full text of DOI:10.1021/ol016250h

ORGANIC
LETTERS
2001
Vol. 3, No. 25
3995-3998
Efficient Strategy for the Synthesis of
Stereopentad Subunits of Scytophycin,
Rifamycin S, and Discodermolide
S. BouzBouz* and J. Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 - Paris Cedex 05, France
janine.cossy@espci.fr
Received June 8, 2001 (Revised Manuscript Received October 30, 2001)
ABSTRACT
An efficient, simple method has been developed for the stereocontrolled synthesis of polypropionate stereopentads in high enantio- and
diastereomeric purities.
The polypropionates (chains with alternating methyl-hy-
droxy-methyl substituents)1 represent an important class of
natural products such as the macrolides and the ionophores,2
which are often associated with a broad spectrum of
biological activity. Their name comes from their biogenesis,
which entails the iterative condensation of propionate units.3
Several stereoselective methods and strategies have been
developed to provide access to these systems which possess
a high density of stereogenic centers.4,5
The presence of more than one stereopentad encompassing
multiple contiguous stereogenic centers and the control of
absolute stereochemistry in a given molecule presents a major
challenge in stereoselective synthesis. In looking for routes
to prepare advanced stereopentad segments, our interest was
drawn to meso-dialdehydes.6 The asymmetric transformation
of meso compounds by reaction with a chiral reagent is a
generally useful strategy for asymmetric synthesis, and in
recent years several reactions of this type involving either
enzymatic catalysis or nonenzymatic reactions have been
reported.7
We report here the direct transformation of meso-dialde-
hydes 1a and 1b to stereopentad subunits by using the
cyclopentadienyldialkoxycrotyltitanium8 complexes (R,R)-
II and (S,S)-II and their further elaboration to common
polypropionate subunits present in different natural products
(4) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Masamune, S.;
Choy, W. Aldrichimica Acta 1982, 15, 47. (c) Mukaiyama, T. Org. React.
1982, 28, 103. (d) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982,
21, 555. (e) Heathcock, C. H. Aldrichimica Acta 1990, 23, 99. (f) Paterson,
I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797. (g) Paterson, I.; Yeung,
K. S. Tetrahedron Lett. 1993, 34, 5347. (h) Szymoniak, J.; Lefranc, H.;
Mo¨ıse, C. J. Org. Chem. 1996, 61, 3926. (i) Marshall, J. A.; Palovich, M.
R. J. Org. Chem. 1998, 63, 3701. (j) Marshall, J. A.; Fitzgerald, R. N. J.
Org. Chem. 1999, 64, 4477.
(5) (a) Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59. (b) Hanessian,
S. Aldrichimica Acta 1989, 22, 3. (c) Marshall, J. A.; Perkins, J. F.; Wolf,
M. A. J. Org. Chem. 1995, 60, 5556. (d) Vogel, P.; Sevin, A.-F.; Kernen,
P.; Bialecki, M. Pure Appl. Chem. 1996, 68, 719. (e) Jain, N. F.; Takenaka,
N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475.
(1) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(2) For reviews, see: (a) O’Hagen, D. The Polyketide Metabolites; Ellis
Horwood: Chichester, 1991. (b) Schummer, D.; Bo¨hlendorf, B.; Kiffe, M.;
Ho¨fle, G. In Antibiotics and AntiViral Compounds; Krohn, K., Kirst, H.
A., Maag, H., Eds.; VCH: Weinheim, 1993. (c) O’Hagen, D. Nat. Prod.
Rep. 1995, 12, 1. (d) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod.
Rep. 1995, 12, 165.
(3) See, for example: (a) Corey, E. J.; Cheng, X. M. The Logic of
Chemical Synthesis; Wiley: New York, 1989. (b) The Total Synthesis of
Natural Products; Ap Simon, J. A., Ed.; Wiley: New York, Vols. 1-8.
(c) Studies in Natural Product Synthesis; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, Vols. 1-13. (d) Recent Progress in The Chemical Synthesis
of Antibiotics and Related Microbial Products; Lukacs, G., Ed.; Springer-
Verlag: Heidelberg, 1993; Vol. 2. (e) Macrolides-Chemistry, Pharmacology
and Clinical Uses; Bryskier, A. J., Butzler, J.-P., Neu, H. C., Tulkens, P.
M., Eds.; Arnette Blackwell: Paris, 1993, (f) Antibiotics and AntiViral
Compounds, Chemical Synthesis and Modification; Krohn, K., Kirst, H.
A., Maag, H., Eds.; VCH: Weinheim, 1993.
(6) De Brabander, J.; Oppolzer, W. Tetrahedron 1997, 53, 9169.
(7) Kann, N.; Rein, T. J. Org. Chem. 1993, 58, 3802 and references
therein.
(8) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
10.1021/ol016250h CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/14/2001

Figure 1.
such as scytophycin,9 rifamycin S,10 and discodermolide11
(Figure 1).
Treatment of dialdehyde 1a with one equivalent of
crotyltitanium complex (R,R)-II and (S,S)-II was first
examined. The hemiketals 2a and 2b were respectively
obtained, and these crude products were treated with NaBH4
to produce stereopentads 3a12 (54% from 1a) and 3b12 (56%
from 1a). It is worth noting that in these experiments the
double addition products were not observed (Scheme 1).
The relative stereochemistry between the different groups
present in 3a and 3b was determined after transformation
of these compounds to the corresponding acetonides 6a and
Scheme 1
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Org. Lett., Vol. 3, No. 25, 2001

6b. Esterification of the primary alcohol 3a with pivaloyl
chloride led to 4a in 91% yield, followed by treatment of
compound 4a with tetra-n-butylammonium fluoride (nBu4-
NF) (94%). Subsequent protection of diol 5a with 2,2-
dimethoxypropane in the presence of CSA in acetone afford
the acetonide 6a in 92% yield. A similar reaction sequence
was applied to stereopentad 3b to afford acetonide 6b
(Scheme 2). The relative stereochemistry of the anti-1,3-
Scheme 4
Scheme 2
The stereopentad 9 present in the C15-C21 fragment of
(+)-discodermolide was synthesized from the meso-dialde-
hyde 1b15 by using the cyclopentadienyldialkoxycroty-
ltitanium complex (R,R)-II. When dialdehyde 1b was treated
with (R,R)-II, lactol 8 was obtained and directly reduced with
NaBH4 (MeOH, 0 °C) to afford the stereopentad 9 in 58%
yield. This compound was then transformed to acetonide 11
in three steps. After protection of the primary alcohol by
using pivaloyl chloride (PivCl, pyridine, 25 °C), ester 10
was treated with nBu4NF and the diol was protected under
the standard conditions (CSA, acetone, DMP) to produce
the acetonide 11 in 85% yield. The syn relative configuration
of the hydroxy groups at C3 and C5 was confirmed by the
analysis of the 13C NMR spectra (δ ) 19.2, 29.8 for Me2C).13
The absolute configuration of the stereogenic centers was
determined after transformation of 11 to 12 and by com-
diol in 6a and 6b was confirmed by analyzing the 13C NMR
chemical shift (δ ) 25.0, 23.2 for Me2C).13 The only product
obtained in each case was the Felkin-Anh product.
The absolute configuration at C2, C3, C4, C5, and C6 in
3a was determined after transformation of compound 6a to
the corresponding acetonide 7a (Scheme 3). After reduction
Scheme 3
parison of the [R]D ([R]22D ) +21, c 1.4, CHCl3; lit:16 [R]22
D
) +23.4, c 1.37, CHCl3) (Scheme 4).
As previously observed in the desymmetrization of meso-
dialdehydes by cyclopentadienyldialkoxyallyltitanium com-
(10) Hanessian, S.; Wang, W.; Yonghua, G.; Olivier, E. J. Am. Chem.
Soc. 1997, 119, 10034 and references therein.
(11) (a) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823 and references therein. (b)
Paterson, I.; Gordon, J. F. Tetrahedron Lett. 2000, 41, 6935.
(12) The diastereoselectivity was determined by H NMR and by GC/
MS.
(13) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945.
(14) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
(15) (a) Prepared from the corresponding monoprotected triol. Harada,
T.; Inoue, A.; Wada, I.; Uchimura, J.-J.; Tanaka, S.; Oku, A. J. Am. Chem.
Soc. 1993, 115, 7665. (b) 1H NMR of 1b δ: 9.80 (s, 2H), 4.56 (t, J ) 4.4
Hz, 1H), 2.57 (m, 2H), 1.11 (d, J ) 7.0 Hz, 6H), 0.88 (s, 9H), 0.08 (s, 6H).
(16) Panek, J. S.; Takenaka, N.; Hu, T. J. Am. Chem. Soc. 1999, 121,
9229.
of 6a with LiAlH4 and protection of the primary alcohol by
using TBDPSCl (DMF, imidazole), compound 7a was
1
obtained in 82% yield ([R]22 ) +16.1, c 1.1, CHCl3; lit.14
D
[R]22 ) +18.1, c 1.4, CHCl3). This chemical correlation
D
allowed us to attribute the configuration 2S,3S,4S,5S,6S to
compound 3a. The stereopentad 3a corresponds to the C19-
C25 fragment of scytophycin and to the C4-C10 fragment
of rifamycin S.
(9) Paterson, I.; Watson, C.; Yeung, K.-S.; Ward, R. A.; Wallace, P. A.
Tetrahedron 1998, 54, 11935 and 11955.
Org. Lett., Vol. 3, No. 25, 2001
3997

plexes,17 the cyclopentadienyldialkoxycrotyltitanium com-
plexes (R,R)-II and (S,S)-II discriminate respectively the pro-
(S) and the pro-(R) faces of meso-dialdehydes. The desym-
metrization of meso-dialdehydes by the complexes (R,R)-II
and (S,S)-II allow a short and efficient synthesis of stereo-
pentads which are present in biologically active natural
products.
Acknowledgment. COST D13/010/00 is acknowledged
for support and Eli Lilly (Indianapolis, IN) is greatly
acknowledged for financial support.
Supporting Information Available: Experimental pro-
cedure, analytical and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) BouzBouz, S.; Popkin, M. E.; Cossy, J. Org. Lett. 2000, 2, 3449.
OL016250H
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Org. Lett., Vol. 3, No. 25, 2001